PT88093B - PROCESS FOR THE PREPARATION OF NEW 4-PIPERIDINOALCILLARY DERIVATIVES - Google Patents

Abstract

The derivs. of 4-piperidinyl alkyl urea of formula (I) and their acceptable salts, for use as specific antagonists of the H1 receptors of histamine, are made by reaction of 4-piperidinyl alkyl amines with isocyanates.

Description

The current availability of antihistamines lacking central effects has led to a major therapeutic advance and has again cited an increasing interest in the development of new structures that exhibit this peculiarity. The enormous differences in chemical structure, specificity of action, etc., in non-sedative Hj antagonists, hinder the search for the structure-activity relationship and it seems that, so far, it is chance that determines that a molecule converges both. properties, antihistamines and inability to cross the blood-brain barrier, the latter depending on its ubiquity liposome.

On the other hand, most of the classic antihypertensive drugs also show serotonergic antagonism, anticoinergic activity and blockade of alpha-adrenergic receptors, responsible for certain side effects, linked to the main activity, which limit their own therapeutic performance. r.

For this reason, the search for new antihistamine molecules is directed towards the synthesis of a pure Hj antagonist - which

-2 has a greater affinity for peripheral receptors than for central receptors - a property that is intensified if the drug shows difficulty in crossing the blood-brain barrier - and little or no antagonistic activity for other biochemical amines.

Some 4-piperidino alkanamine derivatives have high activity as specific antagonists of histamine receptors.

The present invention relates to a process for the preparation of new 4-piperidino alkanamine derivatives that can be used successfully in the treatment of allergic manifestations.

The 4-pi peri di noal canamines are reacted with an Isocia. cream, of general formula R3 (CH?) _m NCO, to obtain urea derivatives, of general formula

R _] - N

< ^CH 2> n ^NHZ < ^CH 2> n, ^R 3 in which

R- | represents an organic (C1 -C4) alkyl, cyclic (C1 -Cg), aryl, or roary acidic, such as methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, 2-phenylethyl, phenylmethyl, 2-piperidinyl-methyl, 3-piperidin-1-methyl, 4-piperidin-1-methyl, 4-phenyl-4-hydroxy-butyl, etc. as well as the radicals correspondingly substituted in the aromatic ring by

CH _3> ^C 2 ^H 5 'ON.OCl · ^, CF3, F, Cl, Br, I, NH ^, NO ^ and others;

Z represents a CONH radical;

R ₂ represents a hydroxy group (OH) or a hydrogen atom (H);

n represents the number 0, 1 or 2;

m represents the number 0, 1 or 2;

R3 represents an aralic radical, at 1 ch 1 ar τ '1 ico, alkyl-heteroaryl or heteroaryl, which, in turn, may contain substituents on the aromatic ring, such as CH ^ C ₂ H ₅ , OCH ₃ , 0CF ₃ , OH, F, Cl, Br, I, NH _2> NR ^ R ^, COOH, OCOCH _3> N0 ₂ , (R ^, R ₃ -aceti10, sulfonyl, CH _3> H).

So for example: 4-chlorophenyl-methyl, 4-methylphenyl-methyl; 4-hydroxyphenyl-methyl, 4-fluorophenyl-methyl, 4-acetyloxyphenyl-methyl, 4-methoxyphenyl-methyl, 3-chlorophenyl-methyl, 3-methyl-phenyl-methyl, 3-hydroxy-phenyl-methyl, 3-fluorc> phenyl-methyl, 3- acetyloxyphenyl-methyl, 3-methoxyphenyl-methyl, 2-chlorophenyl-methyl, 2-methylphenyl-methyl, 2-hydroxyphenyl-methyl, 2-fluorophenyl-methyl, 2-acetyloxyphenyl-methyl, 2-methoxyphenyl-methyl, 2- thiophenomethyl, 3-thiophenomethyl, 2-thiophene-etheni10, 2- (3-thiophenyl1) -ethylene, 2-furanomethyl, 3-furanomethyl, 2-pyridyl-methyl, 3-pyridyl-methyl, 4-pyridyl-methyl, 2- phenyl-ethyl, 2-thiophenyl, 3-thiophenyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl0, 4-hydroxyphenyl 10, 2-thiazolyl, 5-thiazo1yl, 2- (3-methyl) ) -1iopheni10, 2- (5-methyl) -1iopheni10, 2- (3-methoxy-5-methyl) -thiophenyl, 2- (3-methoxy-5-phenyl) -1 i ofenyl-2- (3-methylsulfonylamino ) -thiophenyl, 2- (3-methylsulfoni1aminometi1) -1iopheni10, 5- (2,4 - dimethyl) -1iazo1i10 and others.

R ^ may also represent a carboxylic or heterocyclic radical, with greater or lesser unsaturation, such as: cyclohexyl, 1-cyclohexeni1, cycl 1 ope nti 1 o, 1 - cj_ clopenteni1 o, 2-tetrahydrothiofeni1 o, 2-tetrahydrothiofemi '1-methyl, 2-tetrahydro-drofuran 1 and others.

The 4-piperidinoalkanamines used in the process according to the present invention are compounds that are for the most part sufficiently described in the literature. Some, such as 1 - (1-methyl 1-ethyl 1) -4-pi peri-namin, 1-methyl 1 -4-hi droxy-4-amethyl-piperidine, l- (3-pyridyl-methyl) -4-aminopiperidine, etc. , are not described in the literature, however they can be prepared with high yields according to the methods described in the bibliography, such as: NH Harper et al. £ J. Med. Chem .. 7 (6), 729 (1 964or G. Regnier, ^ Chim. Ther. 3, 185, (1 969) _7 from easily feasible compounds such as ethyl acrylate, isopropylamine, methylamine, 3 -aminomethyl-pyridine, etc., which become the corresponding 4-N-substituted piperidinones, by reducing their maximum levels, the 4-pi peridinamines derivatives are obtained (where the symbol R ^ represents a hydrogen atom The reaction between 4-piperidinones and nitromethane, a process also described in the bibliography, G. Regnier [Chim. Ther. 174, (1 969) J, allows to obtain 4-hydroxy-4-nitromethyl 1 piperidines, which upon reduction with Zn / H ⁺ £ Be 1g.818.471J provide 4-hydroxy-4-aminomethyl piperidine derivatives (wherein R4 represents a hydroxy group).

The reduction of 4-piperidinones with NaBH ^ and subsequent treatment of the 4-piperidinol obtained with p-toluenesulfonyl chloride and KEN allows to obtain the 4-cyanopiperidines that are reduced

-5with LiAlH ^ to obtain the 4-pi peri di nometanami in the corresponding currents such as 1 - (1-methyl 1) -4-piperidinomethanamine or 1- (2-phenylethyl) -4-piperidinomethanamine .

The aromatic or alkylated isocyanates used for the preparation of the compounds of formula I (in which the symbol Z represents a CONH group) are prepared according to the process described by H. Ulrich et al. Synthesis, 277 (1979).

The reaction between isocyanates of the general formula R ₃ (CH ₂ ) _m NC0 and 4-piperidinoalkanamines is carried out in an inert solvent such as ethyl acetate, toluene, ethyl ether or tetrahydrofuran, at temperatures between 0 ° and 20 ° C and for time intervals between 1 and 24 hours.

EXAMPLES

The following examples serve only to illustrate the process according to the present invention, so that all details that do not affect its content can be changed and in no case can they be considered as limiting the present invention.

Example 1. N-4-Hydroxyphenyl-N'- £ l- (2-phenyl-ethyl-4-piperidinyl-Z-urea

To a solution of 0.11 mole of 4-hydroxyphenyl isocyanate in 150 ml of ethyl acetate at 20 ° C, a 0.11 mole solution of 1 - (2 -phenyl-ethyl) -4-piperidinamine in 100 ml of ethyl acetate. The reaction mixture is stirred at 20 ° C for 3 to 4 hours, the resulting solid compound is filtered, washed with hexane and recrystallized from an ethanol / hydrochloric acid mixture.

Hydrochloride yield: 55% (P. F.:148°-150°C).

-6Example 2. N-4-Hydroxyphenyl-N'-Z ~ 1 - {methyl 1-ethyl) -4-piperidine 1-ure a

Using a process similar to that described in Example 1, the aforementioned compound is obtained from the 4-hydroxyphenyl isocyanate and 1 - (1-methyl 1-ethyl 1) -4-pi perinine. Yield 50 # [?. F. (HCl): 260-2 (d) ° c.

Claims (5)

Claims 1.- Process for the preparation of new 4-piperidinoalkylurea derivatives of the general formula (CH-.) NHZ (CH-,) R, 2 n 2 m 3 in which it preferably represents an alkyl (C-C ^), alicyclic (C ^ -Cg), alkylaryl or alkyl-heteroaryl radical, as well as those resulting from the substitution of the aromatic nucleus with atoms and groups chosen from CH ₃ , C ₂ H ₅ , OH, OCH ₃ , CF ₃ , F, Cl, Br, I, NH ₂ and NO ₂ , such as: m.ethyl, ethyl, propyl, isopropyl, cyclopentyl, cyclohexyl, 2-phenylethyl , 2-piperidinyl-methyl, 3-piperidinyl-methyl, 4-piperidinyl-methyl, 4-phenyl1-4-hydroxy-butyl, 4-methoxyphenyl-4-hydroxy-butyl, 4-methoxyphenyl-ethyl; / Z represents a CONH group; n represents the number 0.1 or 2; m represents the number 0.1 or 2; represents a hydroxy group or a hydrogen atom; R ^ preferably represents an aryl, alkylaryl, alkyl-heteroaryl or heteroaryl radical, as well as those resulting from substitution in the aromatic nucleus with CH ₃ , C ₂ H ₅ , OH, OCH ₃ , CF ₃ , F, Cl, Br, I , NH, NHCOCH ₃ , nhso ₂ ch ₃ , n (ch ₃ ) so ₂ ch ₃ , no ₂ , cooh, ococh ₃ , n (Ch ₃ ) ₂ and others such as: 4-chlorophenyl-methyl, 3-chlorophenylmethyl , 2-chlorophenylmethyl, 4-hydroxyphenyl, 4-hydroxyphenylmethyl, 3-hydroxyphenylmethyl, 2-hydroxyphenylmethyl, 4-acetyloxyphenylmethyl, 3-acetyloxyphenylmethyl, 2-acetyloxyphenylmethyl, 4-fluorophenyl 1 methyl, 3-fluorophenyl 1methyl, 2-fluorophenyl-1-methyl, 4-methyl-1-phenyl-1-methyl 1-phenyl 1 -m.ethyl, 2-methylphenyl-methyl, 4-methoxyphenyl-methyl, 3-methoxyphenyl-methyl, 2-methoxyphenyl-1-methyl, 2-thiophenomethyl, 3-thicphenomethyl, 2-thiophenethyl, 2- (3-thiophen11) ethenyl, 2-furanmethyl, 3-furanomethyl 2-pyridyl-methyl, 3-pyridyl-methyl, 4-pyridyl-methyl, 2-phenyl-ethenyl, 2-thiophenyl, 3-thiophenyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 5- thiazolyl, 2- (3-methyl) -thiophenyl, 2- (5-methyl-1) -thiophenyl, 2- (3-methoxy-5-methyl) -thiophenyl, 2- (3-methoxy-5-phenyl) - thiophenyl, 2- (3-methylsulfonylaminomethyl) -thiophenyl, 2- (3-methyl sulfonylamino) -thiophenyl, 5- (2,4-dimethyl-thiazolyl), cyclohexyl, cyclopentyl, 1-cyclohexenyl, 1-cyclo-pentenyl, cyclohexylmethyl , 1- (cyclohexenyl) -methyl, cyclopentylmethyl, 1- (cyclopenteni1) -methyl, 2-tetrahydrothiophenyl, 2-tetrahydrofuranyl, 2-tetrahydrothiophenyl-methyl, 2-tetrahydrofurani1-methyl, 4-dimethylaminopheni1 2-aminophenylmethyl, and others, characterized in that an isocyanate of the general formula is reacted R-, (CH_) NCO 3 2 m in which R ^ and m have the meanings defined above, with a 4-piperidinoalkanamine of general formula in which R, R ^ and n have the meanings defined above. 2. Process according to claim 1 for the preparation of compounds of general formula I, characterized in that the reaction between the isocyanate of general formula RCO2) NCO and 4-piperidinoalkanamine take place in a suitable anhydrous solvent, such as ethyl acetate, toluene, ethyl ether or tetrahydrofuran. 3.- Process according to claim 1, for the -10 preparation of compounds of general formula I, characterized in that the isocyanates used for the reaction with the 4-piperidinoalkanamines are: 4-hydroxyphenyl-isocyanate, 3 hydroxy-phenyl-isocyanate, 2-hydroxy-phenyl-isocyanate, 4-acetyloxyphenyl-isocyanate , 3-acetyloxypheni1-isocyanate, 2-acetyloxypheni1-isocyanate, 4-chloro-isocyanatomethylbenzene, 3-chloro-isocyanatomethylbenzene, 2-chloro-isocyanatomethylbenzene, 4-fluoro-isocyanatomethylbenzene, 3-fluoroethylene. 2-fluoro-isocyanatometilbenzene, 4-methoxy-isocyanatomethylbenzene, 3-methoxy-isocyanatomethylbenzene, 2-methoxy-isoeyanatomethylbenzene, 4-dimethylamino-isocyanatomethylbenzene, 4-nitro-isoci-anatomyethylbenzene, 2-nitro-isocyanethylbenzene, 2 2-nitro-isocyanatomethylbenzene, 2-isocyanatomethyl-1-thiophene, 3- isocyanatometi1-thiophene, 4-hydroxy-isoeianatoethylbenzene, 4- acetyloxy-isocyanatoethylbenzene, 2-isocisnatoethylthiophene, 3-isocyanatoeteni1-thiophene, isocyanato-cyclohexane, isocyanato-cyclopentane, isocyanatomethyl-cyclohexene, isocyanatomethyl-cyclopentene, 2-isocyanatomethi1-tetrahydrothiophene. 4. A process according to claims 1, 2 and 3 for the preparation of compounds of general formula I, characterized in that the 4-pioeridino alkanamines used are: 1- (2-phenylethyl) -4-piperidinoamine, 1-phenylmethyl-4-piperidinoamine, 1-methyl-4-piperidinoamine, 1-ethyl-4-piperidinoamine _? 1- (1-methylethyl} -4-piperidinoamine, l-cyclohexyl-4-piperidinc-11X amine, 1-cyclopenti1-4-piperidinoamine, l- (4-phenylbutyl-4-hydroxy) -4-piperidinoamine, 1— ( 2 — phenylethyl) -4-piperidinemethanamine, 1-phenylmethyl-4-pipiridinemethanamine, 1-methyl-4-piperidinemethanamine, 1-ethyl1-4-piperidinemethanamine, l- (l-methylethyl) -4-piperidinemethanamine, 1-cyclohexi1-4 -piperidinomethanamine, 1-cyclopentyl-4-piperidinomethanamine, 1- (4-phenylbutyl-4-hydroxy) -4-piperidinemethanamine, 1- (2-phenylethyl) -4-hydroxy-4-aminomethyl-piperidine, 1-phenylmethyl1-4 -hydroxy-4-aminomethyl-piperidine, 1-methyl-4-hydroxy-4-amincmethyl-piperidine, 1-ethyl1-4-hydroxy-4-aminomethyl-piperidine, 1- {1-methylethyl) -4-hydroxy-4 -aminomethylpiperidine, 1-cyclohexyl-4-hydroxy-4-aminomethyl-1-piperidine, 1-cyclopenti1-4-hydroxy-4-aminomethyl-1-piperidine, l- (4-phenylbutyl-4-hydroxy) -4-hydroxy-4- aminomethyl 1-piperidir.a, 1- (2-phenylethyl) - 4-piperidinoethanamine, 1-methyl-4-piperidinoethanamine, 1-phenylmethyl 1-4-piper idinoethanamine na, 1- (1-methylethyl) - 4- piperi dinoethanamine, 1-cyclohexy1-4-piperidinoethanamine, 1-cyclopentyl-4-piperidincethanamine, l- (4-phenylbutyl-4-hydroxy) -4-piperidinoethanamine. 5.- Process according to claim 1, for the preparation of: - N-4-hydroxyphenyl 1-N '- / 1-yl 2-phenylethyl 1) -4-hydroxy-4-piperidine 1 J-methyl-urea. N-4-hydroxyphenyl-N'1- (2-phenylethyl) -4-piperidinyl J-urea. N-4-hydroxyphenyl-N ¹ -Γ 1- (2-phenylethyl) -4-piperidinyl / -methyl-urea. N-4-hydroxyphenyl-N'- £ 1- (1-methylethyl) -4-piperidinily-urea, N-4-hydroxyphenyl-N '- (1-methyl-4-piperidinyl) -urea, N-4-hydroxyphenyl -N '- (1-phenylmethyl1-4-piperidinyl) -urea _? N-4-hydroxyphenyl-N'1- (4-hydroxy-4-phenylbutyl) -4-piperidinyl y-urea, N- (4-hydroxy phenyl) - ~ ethyl-N'1- (2-phenylethyl) -4-piperidinyl J-urea, N- (4 - chlorophen i 1) --.et i 1-N ¹ - £ 1- (2-phenylethyl) -4-piperidinyl J-urea, N- (4-fluorophenyl) -r.ethyl-N ¹ 1- (2-phenylethyl) -4-piperidinyl J-urea, N- (4-acetyloxyphen 1) -raeti 1-N '1- (2-phenylethyl) -4-piperidinyl J-urea, N- (4-hydroxypheni 1) - r.et i 1-N ¹ - / 1- (4-h id roxi - 4 - phen i lbut i 1) - 4-piperidinyl y-urea, N- (4-chlorophenyl) -r.etii-N'-y 1- (4-hydroxy-4-pheni ibu111’-4-tipericinyl / -urea, N- (4-fluoropheni1) - ~ et i1-Ν '' - £ 1-í 4-hydroxy-4-phenyl Ibut i1 / - 4 -pipericinyl y-urea,; - (4-acetyl loxy f en 11 · - r .et i 1-N '- / 1- (4-hydroxy-4-phenylbut i1 pi peridinily-urea, K -4-acetoxypheni 1-N '1- (2-phenylethyl) -4-piperidimyl y-urea, N-4-acetyloxyphenyl-N '- / ’1- (4-hydroxy-4-phenylbutyl) -4-piperidine 1 _7-urea, N->. 4-dirnetylartinopheni 1) - N '1- (2-phenylethyl) - 4-piperidinyl y — urea, N- (4-aminophenyl) -N'- / 1- (2-phenylethyl) -4-pi peridini iy-urea, -13 / '' —τ ' Ν- (2-dimethylaminophenyl) -Ν ¹ 1- (2-phenylethyl) -4-piperidinyl J-urea, N- (2-aminophenyl) -N'1- (2-phenylethyl) -4-piperidinyl / -urea, and its pharmaceutically acceptable salts, preferably hydrochloride, hydrobromide, tartrate, citrate and maleate, characterized by the fact that correspondingly substituted starting compounds are used, Lisbon, July 22, 1988 Asor.te ΟΗ ·. ·· ιί, s _{; j} Prap-iedarie Ho